Association between 5-HT1A receptor C-1019G, 5-HTTLPR polymorphisms and panic disorder: a meta-analysis.

HTR1A C-1019G polymorphism (rs6295) and serotonin transporter promoter polymorphism (5-HTTLPR) have been linked with panic disorder (PD) in different ethnic backgrounds. Both these polymorphisms are in the promoter regions. However, results are inconsistent and contrasting evidence makes reliable conclusions even more challenging. A meta-analysis was conducted to test whether C-1019G polymorphism and 5-HTTLPR were involved in the etiology of PD. Articles researching the link between C-1019G, 5-HTTLPR polymorphisms, and PD were retrieved by database searching and systematically selected on the basis of selected inclusion parameters. 21 studies were included that examined the relationship of rs6295,5-HTTLPR polymorphisms with PD risk susceptibility (rs62957 polymorphism - 7 articles, and 5-HTTLPR polymorphism - 14 articles). A significant association was seen between the rs6295 polymorphism and PD pathogenesis, especially in Caucasian PD patients. No significant genetic linkage was found between the 5-HTTLPR polymorphism and PD. C-1019G polymorphism was involved in the etiology of PD in Caucasian patients. The 5-HTTLPR polymorphism was not a susceptibility factor of PD.

Neurochemical and genetic factors in panic disorder: a systematic review.

This systematic review addresses the complex nature of Panic Disorder (PD), characterized by recurrent episodes of acute fear, with a focus on updating and consolidating knowledge regarding neurochemical, genetic, and epigenetic factors associated with PD. Utilizing the PRISMA methodology, 33 original peer-reviewed studies were identified, comprising 6 studies related to human neurochemicals, 10 related to human genetic or epigenetic alterations, and 17 animal studies. The review reveals patterns of altered expression in various biological systems, including neurotransmission, the Hypothalamic-Pituitary-Adrenal (HPA) axis, neuroplasticity, and genetic and epigenetic factors leading to neuroanatomical modifications. Noteworthy findings include lower receptor binding of GABAA and serotonin neurotransmitters in the amygdala. The involvement of orexin (ORX) neurons in the dorsomedial/perifornical region in triggering panic reactions is highlighted, with systemic ORX-1 receptor antagonists blocking panic responses. Elevated Interleukin 6 and leptin levels in PD patients suggest potential connections between stress-induced inflammatory changes and PD. Brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) signaling are implicated in panic-like responses, particularly in the dorsal periaqueductal gray (dPAG), where BDNF's panicolytic-like effects operate through GABAA-dependent mechanisms. GABAergic neurons' inhibitory influence on dorsomedial and posterior hypothalamus nuclei is identified, potentially reducing the excitability of neurons involved in panic-like responses. The dorsomedial hypothalamus (DMH) is highlighted as a specific hypothalamic nucleus relevant to the genesis and maintenance of panic disorder. Altered brain lactate and glutamate concentrations, along with identified genetic polymorphisms linked to PD, further contribute to the intricate neurochemical landscape associated with the disorder. The review underscores the potential impact of neurochemical, genetic, and epigenetic factors on the development and expression of PD. The comprehensive insights provided by this systematic review contribute to advancing our understanding of the multifaceted nature of Panic Disorder and pave the way for targeted therapeutic strategies.

Psychological distress and uterine fibroids: a bidirectional two-sample mendelian randomization study.

BACKGROUND: Observational data indicates a connection between emotional discomfort, such as anxiety and depression, and uterine fibroids (UFs). However, additional investigation is required to establish the causal relationship between them. Hence, we assessed the reciprocal causality between four psychological disorders and UFs utilizing two-sample Mendelian randomization (MR). METHODS: To evaluate the causal relationship between four types of psychological distress (depressive symptoms, severe depression, anxiety or panic attacks, mood swings) and UFs, bidirectional two-sample MR was employed, utilizing single nucleotide polymorphisms (SNPs) associated with these conditions. Both univariate MR (UVMR) and multivariate MR (MVMR) primarily applied inverse variance weighted (IVW) as the method for estimating potential causal effects. Complementary approaches such as MR Egger, weighted median, simple mode, and weighted mode were utilized to validate the findings. To assess the robustness of our MR results, we conducted sensitivity analyses using Cochran's Q-test and the MR Egger intercept test. RESULTS: The results of our UVMR analysis suggest that genetic predispositions to depressive symptoms (Odds Ratio [OR] = 1.563, 95% Confidence Interval [CI] = 1.209-2.021, P = 0.001) and major depressive disorder (MDD) (OR = 1.176, 95% CI = 1.044-1.324, P = 0.007) are associated with an increased risk of UFs. Moreover, the IVW model showed a nominally significant positive correlation between mood swings (OR: 1.578; 95% CI: 1.062-2.345; P = 0.024) and UFs risk. However, our analysis did not establish a causal relationship between UFs and the four types of psychological distress. Even after adjusting for confounders like body mass index (BMI), smoking, alcohol consumption, and number of live births in the MVMR, the causal link between MDD and UFs remained significant (OR = 1.217, 95% CI = 1.039-1.425, P = 0.015). CONCLUSIONS: Our study presents evidence supporting the causal relationship between genetic susceptibility to MDD and the incidence of UFs. These findings highlight the significance of addressing psychological health issues, particularly depression, in both the prevention and treatment of UFs.

Epigenetic signatures of social anxiety, panic disorders and stress experiences: Insights from genome-wide DNA methylation risk scores.

Social anxiety disorder (SAD) and panic disorder (PD) are prevalent anxiety disorders characterized by a complex interplay of genetic and environmental factors. Both disorders share overlapping features and often coexist, despite displaying distinct characteristics. Childhood life adversity, overall stressful life events, and genetic factors contribute to the development of these disorders. DNA methylation, an epigenetic modification, has been implicated in the pathogenesis of these diseases. In this study, we investigated whether whole-genome DNA methylation risk scores (MRSs) for SAD risk, severity of social anxiety, childhood life adversity, PD risk, and overall stressful life events were associated with SAD or PD case‒control status. Preliminary epigenome-wide association studies (EWASs) for SAD risk, severity of social anxiety, and childhood life adversity were conducted in 66 SAD individuals and 77 healthy controls (HCs). Similarly, EWASs for PD risk and overall stressful life events were performed in 182 PD individuals and 81 HCs. MRSs were calculated from these EWASs. MRSs derived from the EWASs of SAD risk and severity of social anxiety were greater in PD patients than in HCs. Additionally, MRSs derived from the EWASs of overall stressful life events, particularly in PD individuals, were lower in SAD individuals than in HCs. In contrast, MRSs for childhood life adversity or PD risk were not significantly associated with PD or SAD case‒control status. These findings highlight the epigenetic features shared in both disorders and the distinctive epigenetic features related to social avoidance in SAD patients, helping to elucidate the epigenetic basis of these disorders.

Discrimination between healthy participants and people with panic disorder based on polygenic scores for psychiatric disorders and for intermediate phenotypes using machine learning.

OBJECTIVE: Panic disorder is a modestly heritable condition. Currently, diagnosis is based only on clinical symptoms; identifying objective biomarkers and a more reliable diagnostic procedure is desirable. We investigated whether people with panic disorder can be reliably diagnosed utilizing combinations of multiple polygenic scores for psychiatric disorders and their intermediate phenotypes, compared with single polygenic score approaches, by applying specific machine learning techniques. METHODS: Polygenic scores for 48 psychiatric disorders and intermediate phenotypes based on large-scale genome-wide association studies (n = 7556-1,131,881) were calculated for people with panic disorder (n = 718) and healthy controls (n = 1717). Discrimination between people with panic disorder and healthy controls was based on the 48 polygenic scores using five methods for classification: logistic regression, neural networks, quadratic discriminant analysis, random forests and a support vector machine. Differences in discrimination accuracy (area under the curve) due to an increased number of polygenic score combinations and differences in the accuracy across five classifiers were investigated. RESULTS: All five classifiers performed relatively well for distinguishing people with panic disorder from healthy controls by increasing the number of polygenic scores. Of the 48 polygenic scores, the polygenic score for anxiety UK Biobank was the most useful for discrimination by the classifiers. In combinations of two or three polygenic scores, the polygenic score for anxiety UK Biobank was included as one of polygenic scores in all classifiers. When all 48 polygenic scores were used in combination, the greatest areas under the curve significantly differed among the five classifiers. Support vector machine and logistic regression had higher accuracy than quadratic discriminant analysis and random forests. For each classifier, the greatest area under the curve was 0.600 ± 0.030 for logistic regression (polygenic score combinations N = 14), 0.591 ± 0.039 for neural networks (N = 9), 0.603 ± 0.033 for quadratic discriminant analysis (N = 10), 0.572 ± 0.039 for random forests (N = 25) and 0.617 ± 0.041 for support vector machine (N = 11). The greatest areas under the curve at the best polygenic score combination significantly differed among the five classifiers. Random forests had the lowest accuracy among classifiers. Support vector machine had higher accuracy than neural networks. CONCLUSIONS: These findings suggest that increasing the number of polygenic score combinations up to approximately 10 effectively improved the discrimination accuracy and that support vector machine exhibited greater accuracy among classifiers. However, the discrimination accuracy for panic disorder, when based solely on polygenic score combinations, was found to be modest.

Effects of antidepressant on FKBP51 mRNA expression and neuroendocrine hormones in patients with panic disorder.

OBJECTIVE: The purpose of this study was to investigate the effects of escitalopram on the peripheral expression of hypothalamic-pituitary-adrenal (HPA) axis-related genes (FKBP51, HSP90, NR3C1 and POMC) and HPA-axis hormones in patients with panic disorder (PD). METHODS: Seventy-seven patients with PD were treated with escitalopram for 12 weeks. All participants were assessed for the severity of panic symptoms using the Panic Disorder Severity Scale (PDSS). The expression of HPA-axis genes was measured using real-time quantitative fluorescent PCR, and ACTH and cortisol levels were measured using chemiluminescence at baseline and after 12 weeks of treatment. RESULTS: At baseline, patients with PD had elevated levels of ACTH and cortisol, and FKBP51 expression in comparison to healthy controls (all p < 0.01). Correlation analysis revealed that FKBP51 expression levels were significantly positively related to cortisol levels and the severity of PD (all p < 0.01). Furthermore, baseline ACTH and cortisol levels, and FKBP51 expression levels were significantly reduced after 12 weeks of treatment, and the change in the PDSS score from baseline to post-treatment was significantly and positively related to the change in cortisol (p < 0.01). CONCLUSIONS: The results suggest that PD may be associated with elevated levels of ACTH and cortisol, and FKBP51 expression, and that all three biomarkers are substantially decreased in patients who have received escitalopram treatment.

A causal relationship between panic disorder and risk of alzheimer disease: a two-sample mendelian randomization analysis.

BACKGROUND: Observational studies have suggested a link between panic disorder (PD) and Alzheimer disease (AD). This study aimed to identify the underlying association of PD with the risk of AD using Mendelian randomization. METHODS: Genetic instrumental variables (IVs) were retrieved in the genome-wide association study between PD and AD. Then, five different models, namely inverse variance weighting (IVW), weighted median, weighted mode, MR-Egger and MR-robust adjusted profile scores (MR-RAPS), were used for MR Analysis. Finally, the heterogeneity and pleiotropy of identified IVs were verified by multiple sensitivity tests. RESULTS: The Cochran's Q test based on MR Egger and IVW showed that no evidence of heterogeneity was found in the effects of instrumental variables, so a fixed-effect model was used. IVW analysis (OR 1.000479, 95% CI [1.000147056, 1.000811539], p = 0.005) indicated that PD was associated with an increased risk of AD, and a causal association existed between them. Meanwhile, weighted median (OR 1.000513373, 95% CI [1.000052145, 1.000974814], p = 0.029) and MR-RAPS (OR 1.000510118, 95% CI [1.000148046, 1.00087232], p = 0.006) also showed the similar findings. In addition, extensive sensitivity analyses confirmed the robustness and accuracy of these results. CONCLUSION: This investigation provides evidence of a potential causal relationship between PD and the increased risk of AD. Based on our MR results, when diagnosing and treating patients with PD, clinicians should pay more attention to their AD-related symptoms to choose therapeutic measures or minimize comorbidities. Furthermore, the development of drugs that improve both PD and AD may better treat patients with these comorbidities.

Spatiotemporal expression patterns of anxiety disorder-associated genes.

Anxiety disorders (ADs) are the most common form of mental disorder that affects millions of individuals worldwide. Although physiological studies have revealed the neural circuits related to AD symptoms, how AD-associated genes are spatiotemporally expressed in the human brain still remains unclear. In this study, we integrated genome-wide association studies of four human AD subtypes-generalized anxiety disorder, social anxiety disorder, panic disorder, and obsessive-compulsive disorder-with spatial gene expression patterns. Our investigation uncovered a novel division among AD-associated genes, marked by significant and distinct expression enrichments in the cerebral nuclei, limbic, and midbrain regions. Each gene cluster was associated with specific anxiety-related behaviors, signaling pathways, region-specific gene networks, and cell types. Notably, we observed a significant negative correlation in the temporal expression patterns of these gene clusters during various developmental stages. Moreover, the specific brain regions enriched in each gene group aligned with neural circuits previously associated with negative decision-making and anxious temperament. These results suggest that the two distinct gene clusters may underlie separate neural systems involved in anxiety. As a result, our findings bridge the gap between genes and neural circuitry, shedding light on the mechanisms underlying AD-associated behaviors.

Gene Expression Analysis of nc-RNAs in Bipolar and Panic Disorders: A Pilot Study.

BACKGROUND: Bipolar Disorder (BD) is a chronic, highly disabling mood disorder. Among the major comorbidities, Panic Disorder (PD) is often associated with BD. This could suggest a common genetic and pathophysiological background between these two conditions, as suggested by previous studies. Despite the widespread diffusion of these conditions, little is still known about the exact pathophysiological dynamics that underlies them. Non-coding RNAs have recently started to gain attention in psychiatry research, with several papers indicating the dysregulation of lncRNAs as a possible key factor in etiopathogenesis of several mental disorders. In the light of the above, the aim of this study is to evaluate the gene expression levels of MALAT1, PANDA, GAS5, HOTAIR lncRNAs and miR-221-5p microRNA, which are highly expressed in the CNS, in drug-naïve/drug-free bipolar and panic patients. METHODS: the experimental plan envisaged the recruitment of sixteen patients with a first diagnosis of type one or type two BD and ten patients with PD. Patients with medical and/or psychiatric comorbidities were excluded. Peripheral venous blood was collected both from patients and healthy controls. Each of the patients recruited for the study was prescribed with therapy. Serum ncRNAs levels were remeasured after 5 months of therapy. RESULTS: MALAT-1, GAS-5 and miR-221-5p are significantly up-regulated in BD after therapy, while PD group showed a down-regulation of all the ncRNAs investigated after therapy. CONCLUSIONS: gene expression levels of the ncRNAs miR-221, MALAT1, GAS5, which are implicated in inhibitory modulation of the glucocorticoid receptor, are significantly over-expressed in bipolar patients following therapy, while all ncRNAs are significantly over-expressed in the PD T1 patients group compared with healthy controls. Data concerning PD represent, to our knowledge, a novelty.

The multi-generational familial aggregation of interstitial cystitis, other chronic nociplastic pain disorders, depression, and panic disorder.

BACKGROUND: Interstitial cystitis/painful bladder syndrome (IC) is a chronic pelvic pain condition which has high comorbidity with other nociplastic, or unexplained, pain disorders [e.g. fibromyalgia (FM), irritable bowel syndrome (IBS), and myalgic encephalomyelitis/chronic fatigue (ME/CFS)] and some psychiatric conditions [major depressive disorder (MDD) and panic disorder (PD)]. Here we investigated the shared familiality of IC and these other nociplastic and psychiatric conditions. METHODS: Subjects were identified in the Utah Population Database, which links genealogy data back to the 1800s to medical record diagnosis billing code data back to 1995. We computed the relative risk of each of these disorders among first (FDR), second (SDR), and third-degree relatives (TDR) of six proband groups: IC, FM, IBS, ME/CFS, PD, and MDD. Given the known familial aggregation of each of these disorders, we conducted our analyses to test for heritable interrelationships using proband subgroups whose members did not have the diagnosis assessed in their relatives. RESULTS: We observed strong evidence for heritable interrelationships among all six disorders. Most analyses indicated significantly increased risk for each of the six disorders in FDR, SDR, and TDR of all or most proband groups. Out of 30 possible bidirectional disorder interrelationships, 26 were significant among FDR, 23 were significant among SDR, and 7 were significant among TDR. Clustering was observed in both close and distant relatives. CONCLUSIONS: Our results support a common, heritable component to IC and other nociplastic and psychiatric conditions.

Altered DNA Methylation of the Serotonin Transporter Gene Associated with Early Life Stress and White Matter Microalterations in Korean Patients with Panic Disorder.

INTRODUCTION: Changes in the DNA methylation of 5-HTTLPR are associated with the pathophysiology of panic disorder (PD). This study was conducted to investigate the association between stressful life events and the level of 5-HTTLPR methylation in patients with PD. We also examined whether these factors were associated with white matter alterations in psychological trauma-related regions. METHODS: The participants comprised 232 patients with PD and 93 healthy adults of Korean descent. DNA methylation levels of five cytosine-phosphate-guanine (CpG) sites in the 5-HTTLPR region were analyzed. Voxel-wise statistical analysis of diffusion tensor imaging data was performed within the trauma-related regions. RESULTS: PD patients showed significantly lower levels of the DNA methylation at 5-HTTLPR 5 CpG sites than healthy controls. In patients with PD, the DNA methylation levels at 5-HTTLPR 5 CpG sites showed significant negative association with the parental separation-related psychological distress, and positive correlations with the fractional anisotropy values of the superior longitudinal fasciculus (SLF) which might be related to trait anxiety. CONCLUSION: Early life stress was significantly associated with DNA methylation levels at 5-HTTLPR related to the decreased white matter integrity in the SLF region in PD. Decreased white matter connectivity in the SLF might be related to trait anxiety and is vital to the pathophysiology of PD.

Pathoclinical associations between panic disorders and the brain-derived neurotrophic factor Val66Met polymorphism: an updated meta-analysis.

Prior studies have indicated the pathological role of brain-derived neurotrophic factor (BDNF) gene polymorphism in panic disorders (PD). A functionally less active BDNF Val66Met mutant was previously detected in PD patients with different ethnic backgrounds. However, the results remain inconclusive or inconsistent. A meta-analysis was used to explore the consistency of the BDNF Val66Met mutant's association with PD irrespective of the subject's ethnicity. Relevant case-controlled full-length clinical and preclinical reports were retrieved by database searching, and 11 articles involving 2203 cases and 2554 controls were systematically selected per the standard inclusion criteria. Eleven articles were finally included that explored the relationship between the Val66Met polymorphism and PD risk susceptibility. Statistical analysis revealed a significant genetic association of the mutation, allele frequencies, and genotype distributions of BDNF with PD onset. Our findings demonstrated that the BDNF Val66Met is a susceptibility factor of PD.

Integrated genome-wide methylation and expression analyses provide predictors of diagnosis and early response to antidepressant in panic disorder.

BACKGROUND: We investigated differentially methylated and expressed genes between panic disorder (PD) and healthy controls (HCs) to determine whether DNA methylation and expression level of candidate genes can be used as biomarkers for diagnosis and early response. METHODS: Illumina infiniun Methylation EPIC (850 k) Beadchip for genome-wide methylation screening and mRNA sequencing was conducted in a discovery set (30 patients with PD and 30 matched HCs). The candidate gene loci methylation and expression were verified in an independent validation sample (101 PD patients and 107 HCs). RESULTS: In the discovery set, there were 3613 differentially methylated cytosine phosphate guanosine sites and these differential methylation positions were located within 1938 unique genes, including 1758 hypermethylated genes, 150 hypomethylated genes, and the coexistence of hypermethylation and hypomethylation sites were found in 30 genes. There were 1111 differential transcripts in PD compared to normal controls (850 down-regulated and 261 up-regulated). Further, 212 differentially expressed genes were screened (40 up-regulated and 172 down-regulated). In the validation set, compared with HCs, there was no significant difference in DNA methylation level of Casitas B-lineage lymphoma (CBL) gene loci (cg07123846). The expression level of CBL gene in PD patients was lower (vs. HCs). After four weeks' treatment, the baseline expression level of CBL gene in the responders was higher than nonresponders. LIMITATIONS: The sample size was limited. We only chose CBL as a candidate gene. Follow-up periods were short. CONCLUSIONS: There are differences in genome-wide DNA methylation and mRNA expression between PD patients and HCs. The changes in expression level of CBL gene may be an important molecular marker for PD diagnosis and early response.

Associations of DNA methylation of HPA axis-related genes and neuroendocrine abnormalities in panic disorder.

OBJECTIVE: The purpose of this study was to investigate the role of aberrant DNA methylation of hypothalamic-pituitary-adrenal (HPA) axis-related genes (CRHR1, CRHR2, CRH, FKBP5, HSP90AA1, NR3C1, and POMC) in panic disorder (PD) development. We investigated the correlation among gene methylation levels, adrenocorticotropic hormone (ACTH), cortisol, and PD severity in patients. METHODS: We compared the methylation levels of HPA axis-related genes between 178 patients with PD and 184 healthy controls using MethylTarget. We then measured ACTH and cortisol levels using chemiluminescence. Disease severity was assessed using the Panic Disorder Severity Scale. RESULTS: Compared with healthy controls, patients with PD displayed significantly higher levels of ACTH and cortisol, and significantly reduced methylation levels of CRHR1, FKBP5, HSP90AA1, and NR3C1 after correcting for multiple testing using the false discovery method. A significant positive correlation was observed between the methylation of CRHR1, CRHR2, and NR3C1 and ACTH levels in patients with PD, and methylation levels of CRHR1 and NR3C1 were significantly positively related to cortisol levels. In addition, a negative correlation was observed between PD severity and the methylation of CRH, CRHR1, CRHR2, and HSP90AA1. CONCLUSION: Aberrant methylation of HPA axis-related genes may predict PD development and impact ACTH and cortisol levels.

Effects of stressful life-events on DNA methylation in panic disorder and major depressive disorder.

BACKGROUND: Panic disorder (PD) is characterized by recurrent panic attacks and higher affection of women as compared to men. The lifetime prevalence of PD is about 2-3% in the general population leading to tremendous distress and disability. Etiologically, genetic and environmental factors, such as stress, contribute to the onset and relapse of PD. In the present study, we investigated epigenome-wide DNA methylation (DNAm) in respond to a cumulative, stress-weighted life events score (wLE) in patients with PD and its boundary to major depressive disorder (MDD), frequently co-occurring with symptoms of PD. METHODS: DNAm was assessed by the Illumina HumanMethylation450 BeadChip. In a meta-analytic approach, epigenome-wide DNAm changes in association with wLE were first analyzed in two PD cohorts (with a total sample size of 183 PD patients and 85 healthy controls) and lastly in 102 patients with MDD to identify possible overlapping and opposing effects of wLE on DNAm. Additionally, analysis of differentially methylated regions (DMRs) was conducted to identify regional clusters of association. RESULTS: Two CpG-sites presented with p-values below 1 × 10-05 in PD: cg09738429 (p = 6.40 × 10-06, located in an intergenic shore region in next proximity of PYROXD1) and cg03341655 (p = 8.14 × 10-06, located in the exonic region of GFOD2). The association of DNAm at cg03341655 and wLE could be replicated in the independent MDD case sample indicating a diagnosis independent effect. Genes mapping to the top hits were significantly upregulated in brain and top hits have been implicated in the metabolic system. Additionally, two significant DMRs were identified for PD only on chromosome 10 and 18, including CpG-sites which have been reported to be associated with anxiety and other psychiatric phenotypes. CONCLUSION: This first DNAm analysis in PD reveals first evidence of small but significant DNAm changes in PD in association with cumulative stress-weighted life events. Most of the top associated CpG-sites are located in genes implicated in metabolic processes supporting the hypothesis that environmental stress contributes to health damaging changes by affecting a broad spectrum of systems in the body.

DNA-methylation dynamics across short-term, exposure-containing CBT in patients with panic disorder.

Interaction of genetic predispositions and environmental factors via epigenetic mechanisms have been hypothesized to play a central role in Panic Disorder (PD) aetiology and therapy. Cognitive Behavioral Therapy (CBT), including exposure interventions, belong to the most efficient treatments of PD although its biological mechanism of action remains unknown. For the first time, we explored the dynamics and magnitude of DNA-methylation and immune cell-type composition during CBT (n = 38) and the therapeutic exposure intervention (n = 21) to unravel their biological correlates and identify possible biomarkers of therapy success. We report transient regulation of the CD4 + T-Cells, Natural Killers cells, Granulocytes during exposure and a significant change in the proportions of CD4 + T cells, CD8 + T cells and B-Cells and Granulocytes during therapy. In an epigenome-wide association study we identified cg01586609 located in a CpG island and annotated to the serotonin receptor 3 A (HTR3A) to be differentially methylated during fear exposure and regulated at gene expression level with significant differences between remitters and non-remitters (p = 0.028). We moreover report cg01699630 annotated to ARG1 to undergo long lasting methylation changes during therapy (paired t test, genome-wide adj.p value = 0.02). This study reports the first data-driven biological candidates for epigenetically mediated effects of acute fear exposure and CBT in PD patients. Our results provide evidence of changes in the serotonin receptor 3 A methylation and expression during fear exposure associated with different long-term CBT trajectories and outcome, making it a possible candidate in the search of markers for therapy success. Finally, our results add to a growing body of evidence showing immune system changes associated with PD.

Alterations of oral microbiota in patients with panic disorder.

The main characteristics of panic disorder (PD) include recurrent panic attacks and persistent worry, accompanied by other physical and cognitive symptoms. While recent studies have revealed that gut bacteria play an important role in anxiety and depression, little is known about the relationship between oral microbiota and PD. Therefore, the objective of this study was to explore a possible correlation between oral microbiota and PD. We conducted 16S rRNA sequencing to compare differences in the oral microbiota of patients with PD (n = 26) and healthy controls (n = 40). Patients with PD exhibited higher alpha diversity (abundance and evenness) in their oral microbiota than healthy controls, while analysis of beta diversity revealed that the two groups differed in microbial community composition. Moreover, the relative abundance of 61 genera differed between them. Overall, PD resulted in distinct oral microbial profiles that could be potential diagnostic markers and therapeutic targets.

The C. elegans homolog of human panic-disorder risk gene TMEM132D orchestrates neuronal morphogenesis through the WAVE-regulatory complex.

TMEM132D is a human gene identified with multiple risk alleles for panic disorders, anxiety and major depressive disorders. Defining a conserved family of transmembrane proteins, TMEM132D and its homologs are still of unknown molecular functions. By generating loss-of-function mutants of the sole TMEM132 ortholog in C. elegans, we identify abnormal morphologic phenotypes in the dopaminergic PDE neurons. Using a yeast two-hybrid screen, we find that NAP1 directly interacts with the cytoplasmic domain of human TMEM132D, and mutations in C. elegans tmem-132 that disrupt interaction with NAP1 cause similar morphologic defects in the PDE neurons. NAP1 is a component of the WAVE regulatory complex (WRC) that controls F-actin cytoskeletal dynamics. Decreasing activity of WRC rescues the PDE defects in tmem-132 mutants, whereas gain-of-function of TMEM132D in mammalian cells inhibits WRC, leading to decreased abundance of select WRC components, impaired actin nucleation and cell motility. We propose that metazoan TMEM132 family proteins play evolutionarily conserved roles in regulating NAP1 protein homologs to restrict inappropriate WRC activity, cytoskeletal and morphologic changes in the cell.

Genetic contributions to anxiety disorders: where we are and where we are heading.

Anxiety disorders are among the most common psychiatric disorders worldwide. They often onset early in life, with symptoms and consequences that can persist for decades. This makes anxiety disorders some of the most debilitating and costly disorders of our time. Although much is known about the synaptic and circuit mechanisms of fear and anxiety, research on the underlying genetics has lagged behind that of other psychiatric disorders. However, alongside the formation of the Psychiatric Genomic Consortium Anxiety workgroup, progress is rapidly advancing, offering opportunities for future research.Here we review current knowledge about the genetics of anxiety across the lifespan from genetically informative designs (i.e. twin studies and molecular genetics). We include studies of specific anxiety disorders (e.g. panic disorder, generalised anxiety disorder) as well as those using dimensional measures of trait anxiety. We particularly address findings from large-scale genome-wide association studies and show how such discoveries may provide opportunities for translation into improved or new therapeutics for affected individuals. Finally, we describe how discoveries in anxiety genetics open the door to numerous new research possibilities, such as the investigation of specific gene-environment interactions and the disentangling of causal associations with related traits and disorders.We discuss how the field of anxiety genetics is expected to move forward. In addition to the obvious need for larger sample sizes in genome-wide studies, we highlight the need for studies among young people, focusing on specific underlying dimensional traits or components of anxiety.